Recent metagenomic studies have discovered gut microbiome signatures in colonic tissues from patients with colorectal cancer or adenomas, suggesting a potential causal link between gut microbiome and the development of colorectal neoplasia. Diet clearly plays an important etiological role in colon carcinogenesis. It is long believed that diet is a major determinant of the human gut microbiota composition. Three recent landmark studies have provided compelling evidence supporting this notion, each having found similar microbiome core signatures. Furthermore, human gut microbiome signature or ?enterotype? is strongly associated with an individual?s long-term diet pattern, but not with short-term dietary changes. To date, few studies have comprehensively examined the complex interplay of fecal microbiome, diet, and risk of colon adenoma. Therefore, we propose a metagenomic molecular epidemiology study to address our hypothesis that diet-associated gut microbiome signatures are associated with risk of colon adenoma. This proposal builds upon a relatively large cohort of patients undergoing screening colonoscopy who are being recruited into the parent GI SPORE project for a stool- based methylation biomarker study for early detection of colon adenomas. We aim to: 1) indentify gut microbiome signatures associated with habitual diet; 2) examine the association of gut microbiome signatures with risk of colon adenoma; and 3) assess direct and gut microbiome-mediated effects of diet on risk of colon adenoma. These aims will be accomplished by using the existing Cleveland Risk Factors and Early Detection of Colon Adenoma cohort population, where rich dietary and epidemiological data and pre-screening stool samples are being collected from 1,600 average-risk patients as part of parent Case GI SPORE program.